Protein found to protect breast cancer tumors from chemotherapy

Finding may help women get more effective treatment

About half of women whose breast cancer is treated with standard chemotherapy have their cancer return within five years. Most chemotherapeutic drugs have undesirable side effects, but there has been no way to predict who would benefit and who wouldn't. Fortunately, new research findings at the University of Southern California could change that.

Researchers at the USC/Norris Comprehensive Cancer Center have discovered a new biological marker in tumors that can help indicate whether a woman's breast cancer will respond to the most commonly prescribed chemotherapy drugs.

Amy S. Lee, Ph.D., professor of biochemistry and molecular biology in the Keck School of Medicine of the University of Southern California, isolated the gene for the GRP78 protein (78-kDA glucose-regulated protein) in 1980. It normally helps protect cells from dying, particularly when they are under stress from a lack of glucose. In her current research, Lee finds that breast cancer tumors with high levels of GRP78 are protected from a common chemotherapy regimen based on Adriamycin, a topoisomerase inhibitor. Her findings are published as a "Priority Report" in the August 15 issue of Cancer Research.

"The importance of this study is in its potential to help clinicians who treat cancer," Lee says. "It will help sort out the patients who won't respond to particular treatment regimens and will have a higher chance of cancer recurrence."

Lee and her colleagues analyzed records of 432 women with Stage II or III breast cancer treated at the USC/Norris Cancer Hospital, of whom 209 received Adriamycin-based chemotherapy. Tumor samples were collected from 127 of the women before they received chemotherapy. The samples were analyzed using antibodies to detect and stain GRP78 protein. Review of the samples under a microscope showed that two-thirds (67 percent) of the tumors tested had high levels of GRP78.

Subsequent analysis of the patients' records showed that women whose tumors had higher levels of GRP78 were more likely to have had the cancer recur. That was particularly likely if the women received Adriamycin-based chemotherapy and no further treatment with the chemotherapy drug taxane, regardless of their tumor stage. Likewise, women who had mastectomies followed by Adriamycin-based therapy were more likely to have the cancer return if their tumors had elevated levels of GRP78, compared to identically treated patients with low level of GRP78.

Conversely, the study also suggests that women who received Adriamycin-based therapy followed by additional treatment with taxane had a lower risk of cancer recurrence if their tumors had elevated levels of GRP78.

Lee hopes others will confirm her findings in subsequent research, and that it will eventually lead to a standard laboratory test that can screen all women diagnosed with breast cancer. "GRP78 will be one more bio-marker to help us offer designer medicine – treatments that are tailored to the patient's cancer instead of one-size-fits-all," Lee says.

The study is anticipated to have broad implications since other types of cancers have also been found to have elevated levels of GRP78. To that end, Lee is also collaborating with USC/Norris pathologist Richard Cote, M.D., on a study of the protein's role in prostate cancer.

Lee says the access to specialists from various disciplines was essential. "This research could not have happened without the collaborative environment at the USC/ Norris Comprehensive Cancer Center," she says. Lee's interdisciplinary research team included clinical oncologist Darcy Spicer, M.D., pathologist Peter Nichols, M.D., epidemiologist Mimi C. Yu, Ph.D., biostatistician Susan Groshen, Ph.D., and epidemiology Ph.D. student Eunjung Lee.

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The research was supported by grants from the Leland K. Whittier Foundation and the Susan G. Komen Breast Cancer Foundation.